The success of platinum complexes such as cisplatin and carboplatin as anticancer drugs is well known but these have a limited spectrum of activity, can have toxic side-effects and platinum-resistant tumours can develop.1 For these reasons it is worthwhile to investigate the design of anticancer drugs based on other transition metals. Recently two octahedral RuIII complexes have entered clinical trials.2,3 The RuIII complexes are thought to be reduced to active RuII species in vivo. RuII can be stabilized by π-bonded arene ligands and a range of RuII arene complexes of the type [(η6-arene)Ru(XY)Z)] where XY=chelated diamine, Z=Cl show anticancer activity both in vitro and in vivo.4,5 These complexes can undergo activation via hydrolysis and bind strongly to DNA, a potential target. Arene complexes of the heavier congener OsII can have almost identical geometries to those of RuII but are subtly different. For example OsII chlorido complexes hydrolyse ca. 40× more slowly and the related aqua adducts have pKa values for Os-OH2 which are ca. 1.5 pKa units lower (more acidic) than those of the analogous RuII complexes. Although OsII arene complexes have now been reported which exhibit cancer cell cytotoxicity,6,7 in general they are less potent than Ru arene complexes.
Recently, certain osmium complexes which comprise azopyridine ligand were developed8. However, the two compounds [(η6-p-cymene)Os(Azpy-NMe2)Cl]PF6 and [(η6-bip)Os(Azpy-NMe2)Cl]PF6 displayed poor solubility in water and did not show significant cytotoxicity against the A549 cancer cell line. Although some of the iminopyridine ligands used in the present invention have been reported and used in metal coordination complexes, the only previous report of an osmium arene complex is that of Schmid et al (complex 4b in J Med Chem 2007, 50, 6343-6355) for a specific Paullone derivative which is active against A549, CH1 and SW480. The present invention shows that the nature of the iminopyridine can have unexpected effects on cancer cell cytotoxicity.
Organometallic 2005, 24, 8, 1966-1973 reports on an osmium complex comprising a 2,2′-azopyridine liginad, but there is no disclosure of any pharmaceutical activity.